Pulmonary Toxocariasis Mimicking Invasive Aspergillosis in a Patient with Ulcerative Colitis

A 45-year-old-male who had underlying ulcerative colitis and presented with fever and dry cough. Initially, the patient was considered to have invasive aspergillosis due to a positive galactomannan assay. He was treated with amphotericin B followed by voriconazole. Nevertheless, the patient deteriorated clinically and radiographically. The lung biopsy revealed eosinophilic pneumonia, and ELISA for Toxocara antigen was positive, leading to a diagnosis of pulmonary toxocariasis. After a 10-day treatment course with albendazole and adjunctive steroids, the patient recovered completely without any sequelae. Pulmonary toxocariasis may be considered in patients with subacute or chronic pneumonia unresponsive to antibiotic agents, particularly in cases with eosinophilia.     

Posttranslational Regulation of Human DNA Polymerase ι

Human DNA polymerases (pols) η and ι are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both polη and polι can be monoubiquitinated in vivo. Polη has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated polι revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Polι monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, polι becomes transiently polyubiquitinated via Lys¹¹- and Lys⁴⁸-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to polι occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys¹¹ and Lys⁴⁸ rather than oxidative damage per se.     

Partitioning of knee joint internal forces in gait is dictated by the knee adduction angle and not by the knee adduction moment

Medial knee osteoarthritis is a debilitating disease. Surgical and conservative interventions are performed to manage its progression via reduction of load on the medial compartment or equivalently its surrogate measure, the external adduction moment. However, some studies have questioned a correlation between the medial load and adduction moment. Using a musculoskeletal model of the lower extremity driven by kinematics–kinetics of asymptomatic subjects at gait midstance, we aim here to quantify the relative effects of changes in the knee adduction angle versus changes in the adduction moment on the joint response and medial/lateral load partitioning. The reference adduction rotation of 1.6° is altered by ±1.5° to 3.1° and 0.1° or the knee reference adduction moment of 17 N m is varied by ±50% to 25.5 N m and 8.5 N m. Quadriceps, hamstrings and tibiofemoral contact forces substantially increased as adduction angle dropped and diminished as it increased. The medial/lateral ratio of contact forces slightly altered by changes in the adduction moment but a larger adduction rotation hugely increased this ratio from 8.8 to a 90 while in contrast a smaller adduction rotation yielded a more uniform distribution. If the aim in an intervention is to diminish the medial contact force and medial/lateral load ratio, a drop of 1.5° in adduction angle is much more effective (causing respectively 12% and 80% decreases) than a reduction of 50% in the adduction moment (causing respectively 4% and 13% decreases). Substantial role of changes in adduction angle is due to the associated alterations in joint nonlinear passive resistance. These findings explain the poor correlation between knee adduction moment and tibiofemoral compartment loading during gait suggesting that the internal load partitioning is dictated by the joint adduction angle.     

Fitness Is Strongly Influenced by Rare Mutations of Large Effect in a Microbial Mutation Accumulation Experiment

Our understanding of the evolutionary consequences of mutation relies heavily on estimates of the rate and fitness effect of spontaneous mutations generated by mutation accumulation (MA) experiments. We performed a classic MA experiment in which frequent sampling of MA lines was combined with whole genome resequencing to develop a high-resolution picture of the effect of spontaneous mutations in a hypermutator (ΔmutS) strain of the bacterium Pseudomonas aeruginosa. After ∼644 generations of mutation accumulation, MA lines had accumulated an average of 118 mutations, and we found that average fitness across all lines decayed linearly over time. Detailed analyses of the dynamics of fitness change in individual lines revealed that a large fraction of the total decay in fitness (42.3%) was attributable to the fixation of rare, highly deleterious mutations (comprising only 0.5% of fixed mutations). Furthermore, we found that at least 0.64% of mutations were beneficial and probably fixed due to positive selection. The majority of mutations that fixed (82.4%) were base substitutions and we failed to find any signatures of selection on nonsynonymous or intergenic mutations. Short indels made up a much smaller fraction of the mutations that were fixed (17.4%), but we found evidence of strong selection against indels that caused frameshift mutations in coding regions. These results help to quantify the amount of natural selection present in microbial MA experiments and demonstrate that changes in fitness are strongly influenced by rare mutations of large effect.     

Selection analysis on the rapid evolution of a secondary sexual trait

Evolutionary analyses of population translocations (experimental or accidental) have been important in demonstrating speed of evolution because they subject organisms to abrupt environmental changes that create an episode of selection. However, the strength of selection in such studies is rarely measured, limiting our understanding of the evolutionary process. This contrasts with long-term, mark–recapture studies of unmanipulated populations that measure selection directly, yet rarely reveal evolutionary change. Here, we present a study of experimental evolution of male colour in Trinidadian guppies where we tracked both evolutionary change and individual-based measures of selection. Guppies were translocated from a predator-rich to a low-predation environment within the same stream system. We used a combination of common garden experiments and monthly sampling of individuals to measure the phenotypic and genetic divergence of male coloration between ancestral and derived fish. Results show rapid evolutionary increases in orange coloration in both populations (1 year or three generations), replicating the results of previous studies. Unlike previous studies, we linked this evolution to an individual-based analysis of selection. By quantifying individual reproductive success and survival, we show, for the first time, that males with more orange and black pigment have higher reproductive success, but males with more black pigment also have higher risk of mortality. The net effect of selection is thus an advantage of orange but not black coloration, as reflected in the evolutionary response. This highlights the importance of considering all components of fitness when understanding the evolution of sexually selected traits in the wild.     

中药联合微生态制剂防治呼吸、消化系统病毒病

本文阐述了中药防治病毒病的历史及其应用概况,中药联合微生态制剂防治呼吸、消化系统病毒病的理论依据、临床应用和发展前景。     

A neutron activation technique for manganese measurements in humans

Manganese (Mn) is an essential element for humans, animals, and plants and is required for growth, development, and maintenance of health. Studies show that Mn metabolism is similar to that of iron, therefore, increased Mn levels in humans could interfere with the absorption of dietary iron leading to anemia. Also, excess exposure to Mn dust, leads to nervous system disorders similar to Parkinson's disease. Higher exposure to Mn is essentially related to industrial pollution. Thus, there is a benefit in developing a clean non-invasive technique for monitoring such increased levels of Mn in order to understand the risk of disease and development of appropriate treatments.To this end, the feasibility of Mn measurements with their minimum detection limits (MDL) has been reported earlier from the McMaster group. This work presents improvement to Mn assessment using an upgraded system and optimized times of irradiation and counting for induced gamma activity of Mn. The technique utilizes the high proton current Tandetron accelerator producing neutrons via the ⁷Li(p,n)⁷Be reaction at McMaster University and an array of nine NaI (Tl) detectors in a 4π geometry for delayed counting of gamma rays. The neutron irradiation of a set of phantoms was performed with protocols having different proton energy, current and time of irradiation. The improved MDLs estimated using the upgraded set up and constrained timings are reported as 0.67 μgMn/gCa for 2.3 MeV protons and 0.71 μgMn/gCa for 2.0 MeV protons. These are a factor of about 2.3 times better than previous measurements done at McMaster University using the in vivo set-up. Also, because of lower dose-equivalent and a relatively close MDL, the combination of: 2.0 MeV; 300 μA; 3 min protocol is recommended as compared to 2.3 MeV; 400 μA; 45 s protocol for further measurements of Mn in vivo.     

Quantitative comparison between the commercial software STRATOS® by Philips and a homemade software for voxel-dosimetry in radiopeptide therapy

BackgroundTargeted radionuclide therapy is a rapidly growing modality. A few commercial treatment planning systems are entering the market. However, some in-house systems are currently developed for a more flexible and customized dosimetry calculation at voxel-level. For this purpose, we developed a novel software, VoxelMed, and performed a comparison with the software STRATOS.MethodsThe validation of both of them was undertaken using radioactive phantoms with different volume inserts. A cohort of 10 patients was also studied after a therapeutic administration of ¹⁷⁷Lu-labelled radiopeptides. The activity, number of disintegrations, absorbed dose and dose-volume histogram (DVH) were calculated for the phantoms and the kidneys in patients, which were the main critical organs at risk in this study.ResultsIn phantoms the absorbed doses computed with VoxelMed and STRATOS agree within 5%. In patients at the voxel-level the absorbed dose to kidneys (VoxelMed: mean 0.66 Gy/GBq) showed a limited difference of 5%, but with a remarkable range (−40%, +60%) between the two software packages. Voxel-dosimetry allows to estimate the dose non-homogeneities in volumes, which may be evaluated through DVHs.ConclusionThis study demonstrates that a fully 3D voxel-dosimetry with multiple SPECT images is feasible by using home-made or commercial software package and absorbed dose results obtained are similar. The main difference between the studied tools was observed in the activity integration method (effective vs physical half-time to time activity curve tail). We believe that an effective half-time integration method produces a more accurate approximation of clinical uptake and resultant dosimetry.     

Livestock-driven land use change to model species distributions: Egyptian vulture as a case study

Species distribution models (SDMs) are increasingly used to predict species ranges and their shifts under future scenarios of global environmental change (GEC). SDMs are thus incorporating key drivers of GEC (e.g. climate, land use) to improve predictions of species’ habitat suitability (i.e. as an indicator of species occurrence). Yet, most SDMs incorporating land use only consider dominant land cover types, largely ignoring other key aspects of land use such as land management intensity and livestock. We developed SDMs including main land use components (i.e. land cover, livestock and its management intensity) to assess their relative importance in shaping habitat suitability for the Egyptian vulture, an endangered raptor linked to livestock presence. We modelled current and future (2020 and 2050) habitat suitability for this vulture using an organism-centred approach. This allowed us to account for basic species’ habitat needs (i.e. nesting cliff) while gaining insight into our variables of interest (i.e. livestock and land cover). Once nest-site requirements were fulfilled, land use variables (i.e. openland and sheep and goat density) were the main factors determining species’ habitat suitability. Current suitable area could decrease by up to 6.81% by 2050 under scenarios with rapid economic growth but no focus on environmental conservation and rural development. Local solutions to environmental sustainability and rural development could double current habitat suitability by 2050. Land use is expected to play a key role in determining Egyptian vulture's distribution through land cover change but also through changes in livestock management (i.e. species and stocking density). Change in stocking densities (sheep and goats/km²) becomes thus an indicator of habitat suitability for this vulture in our study area. Abandonment of agro-pastoral practises (i.e. below ∼15–20 sheep and goats/km²) will negatively influence the species distribution. Nonetheless, livestock densities above these values will not further increase habitat suitability. Given the widespread impacts of livestock on ecosystems, the role of livestock and its management intensity in SDMs for other (non-livestock-related) species should be further explored.     

How to deal with oxygen radicals stemming from mitochondrial fatty acid oxidation

Oxygen radical formation in mitochondria is an incompletely understood attribute of eukaryotic cells. Recently, a kinetic model was proposed, in which the ratio between electrons entering the respiratory chain via FADH₂ or NADH determines radical formation. During glucose breakdown, the ratio is low; during fatty acid breakdown, the ratio is high (the ratio increasing—asymptotically—with fatty acid length to 0.5, when compared with 0.2 for glucose). Thus, fatty acid oxidation would generate higher levels of radical formation. As a result, breakdown of fatty acids, performed without generation of extra FADH₂ in mitochondria, could be beneficial for the cell, especially in the case of long and very long chained ones. This possibly has been a major factor in the evolution of peroxisomes. Increased radical formation, as proposed by the model, can also shed light on the lack of neuronal fatty acid oxidation and tells us about hurdles during early eukaryotic evolution. We specifically focus on extending and discussing the model in light of recent publications and findings.